Pyrano-, thiopyrano- and cyclohexylquinolines as inhibitors of interleukin 1

ABSTRACT

There are disclosed compounds of the formula ##STR1## wherein X is O, S, SO, SO 2  or CR 1  R 2  ; 
     R 1  and R 2  are each independently hydrogen, lower alkyl, carboxyl, lower alkoxy carbonyl, lower cycloalkyl, phenyl, anphthyl, pyridyl, quinolinyl, pyrazinyl, pyridinyl, pyridazinyl, pyrimidinyl, quinoxalinyl, quinazolinyl or any of the foregoing aryl or hetaryl substituents substituted with halo, lower alkyl, lower alkyl carbonyl, benzoyl, COOR 3 , OR 3 , N(R 3 ) 2 , CON(R 3 ) 2 , SO 3  R 3 , SO 2  N(R 3 ) 2 , phenylsulfonyl, lower alkyl sulfonyl, cyano, nitro or trifluoromethyl; 
     R 3  is hydrogen, lower alkyl or phenyl; 
     R 4  is halo, morpholino, 4-methylpiperazino, R 5  NNHR 6 , R 5  NCH 2  CH 2  OCH 3 , or ##STR2## R 5  is hydrogen or lower alkyl; R 6  is hydrogen, lower alkyl, lower alkanoyl, lower cycloalkyl or phenyl; and 
     R 7  and R 8  are each independently, hydrogen, halo, nitro, lower alkoxy, lower alkyl, cyano, trifluoromethyl, phenyl, carboxy or lower alkoxycarbonyl, with the proviso that when R 1  and R 2  are hydrogen or lower alkyl, R 4  is other than halo. 
     and, by virtue of their ability to inhibit interleukin 1, their use as antiinflammatory agents and in treatment of disease states involving enzymatic tissue destruction.

This is a division of U.S. Ser. No. 183,861 filed 4/20/88 now U.S. Pat.No. 4,851,536, which is a continuation-in-part of U.S. Ser. No. 047,376filed 5/7/87 now abandoned.

This invention relates to novel compounds possessing interleukin 1(IL 1) antagonist activity and having antiinflammatory activity.

Interleukin 1 (IL 1) is a peptide hormone exhibiting a number of immuneand inflammatory actions [Dinarello, Rev. Inf. Dis. 6, 51 (1984)]. IL 1is produced, in response to inflammatory stimuli, by leukocytes such asmacrophages and polymorphonuclear cells, as well as by a variety ofother cell types such as synovial cells, endothelial cells andkeratinocytes, and it mediates several biological responses ofleukocytes on other tissue targets such as bone, articular joints,liver, hypothalamus, and brain.

IL 1 was originally shown to augment the proliferation of T lymphocytesfor which it was named lymphocyte activating factor (LAF), and isbelieved to be important for the generation of T cell-dependent immuneresponses.

There is evidence to suggest a relationship between IL 1 and pathologyin various diseases, particularly immunoinflammatory disorders such asrheumatoid arthritis [Dinarello et al., Ann. Rev. Med. 37, 173 (1986)].IL 1 induces acute inflammatory responses producing soft tissue swelling(edema and erythema) [Granstein et al., J. Clin. Invest., 77, 1010(1986)]. It is a chemoattractant for polymorphonuclear leukocytes (PMN)and induces the activation and migration of these cells into tissues. IL1 also stimulates the production of prostaglandin E₂, a potentinflammatory arachidonic acid metabolite, by a variety of cells andtissues including chondrocytes and synovial cells [Mizel et al., Proc.Nat'l. Acad. Sci., 78, 2474 (1981) and Chang et al., J. Immunol., 136,1283 (1986)] and hypothalamic tissue. This effect on the hypothalamus isthought to be responsible for fever production. IL 1 can inducearticular joint destruction by stimulating the production of a varietyof hydrolytic enzymes (neutral proteases such as collagenase,glycosaminoglycanases, etc.) which degrade cartilage matrix proteins(collagen, proteoglycan, etc.) by synovial cells, chondrocytes, andfibroblasts [Dayer et al., Science, 195, 181 (1977) and Postlethwaite,et al., J. Exp. Med., 157, 801 (1983)]. Furthermore, IL 1 induceshyperproliferation of dermal and synovial fibroblasts and is a potentinducer of bone resorption [Wood et al., J. Immunol., 134, 895 (1985)and Gilman and Kimball, Agents and Actions, 16, 468 (1985)].

Finally, IL 1 mediates acute phase reactions including alterations inplasma divalent cations, increased synthesis by liver cells of acutephase proteins (C-reactive protein, serum amyloid A, etc.) and fever.Accordingly, compounds which have IL 1 antagonist activity and therebyinhibit the biological effects of IL 1 can be advantageously used toblock pathologies in which one or more of these events occur such asrheumatoid arthritis, osteoarthritis and related disorders [Rodnan andSchumacher, eds, "Primer on the Arthritic Diseases" 8 ed. Atlanta,1983], psoriasis and other inflammatory/proliferative skin disorders aswell as diseases in which the secretion of collagenase (and other tissuehydrolysing neutral proteinases) has been implicated as a causativefactor, including periodontal disease, tumor invasiveness, andepidermolysis bullosa [Perez-Tamayo, Amer. J. Pathol., 92, 509 (1978)and Harris and Krane, N. Engl. J. Med., 291, 652 (1974)] and so forth.

It has now been found that certain novel pyrano-, thiopyrano- andcyclohexyl- quinolines antagonize the activity of IL 1, and so areuseful as antiinflammatory agents and in the treatment of pathologieswhose etiology is collagenase-based tissue destruction. The presentinvention provides novel compounds having the formula: ##STR3## whereinX is O, S, SO, SO₂ or CR¹ R² ;

R¹ and R² are each independently hydrogen, lower alkyl, carboxyl, loweralkoxy carbonyl, lower cycloalkyl, phenyl, naphthyl, pyridyl,quinolinyl, pyrazinyl, pyridinyl, pyridazinyl, pyrimidinyl,quinoxalinyl, quinazolinyl or any of the foregoing aryl or hetarylsubstituents substituted with halo, lower alkyl, lower alkyl carbonyl,benzoyl, COOR³, OR³, N(R³)₂, CON(R³)₂, SO₃ R³, SO₂ N(R³)₂,phenylsulfonyl, lower alkyl sulfonyl, cyano, nitro or trifluoromethyl;

R³ is hydrogen, lower alkyl or phenyl;

R⁴ is halo, morpholino, 4-methylpiperazino, R⁵ NNHR⁶, R⁵ NCH₂ CH₂ OCH₃or ##STR4## R⁵ is hydrogen or lower alkyl; R⁶ is hydrogen, lower alkyl,lower alkanoyl, lower cycloalkyl or phenyl; and

R⁷ and R⁸ are each independently, hydrogen, halo, nitro, lower alkoxy,lower alkyl, cyano, trifluoromethyl, phenyl, carboxy or loweralkoxycarbonyl, with the proviso that when R¹ and R² are hydrogen orlower alkyl, R⁴ is other than halo.

The terms "lower alkyl" and "lower alkoxy" refer to moieties having 1 to6 carbon atoms in the carbon chain. The term "lower alkanoyl" refers tothe moiety RCO-- wherein R is an alkyl group having 1 to 6 carbon atoms.The term "lower cycloalkyl" refers to a saturated ring having 4 to 7carbon atoms. The term "halo" refers to fluoro, chloro and bromo.

The especially preferred compounds are those having the formula ##STR5##wherein X is S, SO₂, CHCH₃ or ##STR6## and R⁴ is chloro or ##STR7##

The compounds of the invention can be prepared by the reaction of asuitable cyclohexanone, tetrahydropyran-4-one ortetrahydrothiopyran-4-one with a suitably substituted amino benzoic acidin the presence of a halogenating agent to yield a halogenatedintermediate: ##STR8## followed by reaction of the intermediate soobtained with a suitably substituted R⁴ -containing reactant to yieldthe desired final product: ##STR9##

The starting materials used in the above outlined preparative sequencesare all available commercially or can be prepared by conventionalmethods disclosed in the chemical literature.

The compounds of the invention, by virtue of the ability to antagonizeinterleukin 1, are useful in the treatment of such diseases asrheumatoid arthritis, osteoarthritis, tendinitis, bursitis and similarconditions involving inflammation, as well as psoriasis and otherinflammatory/proliferative skin disorders. Moreover, the compounds areuseful in treating disease states involving enzymatic tissuedestruction, for example, conditions in which collagenase has beenimplicated as a causative factor, such as rheumatoid arthritis jointdestruction, peridontal disease, tumor invasiveness, cornealulcerations, epidermolysis bullosa and the like.

When the compounds of the invention are employed as antiinflammatoryagents, or collagenase inhibitors, they can be formulated into oraldosage forms such as tablets, capsules and the like. The compounds canbe administered alone or by combining them with conventional carriers,such as magnesium carbonate, magnesium stearate, talc, sugar, lactose,pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, low melting wax, cocoa butter and the like.Diluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, tablet-disintegrating agents and the like may be employed. Thecompounds may be encapsulated with or without other carriers. In allcases, the proportion of active ingredients in said compositions bothsolid and liquid will be at least to impart the desired activity theretoon oral administration. The compounds may also be injected parenterally,in which case they are used in the form of a sterile solution containingother solutes, for example, enough saline or glucose to make thesolution isotonic. For topical administration, the compounds may beformulated in the form of dusting powders, solutions, creams, lotions oraerosols in pharmaceutically acceptable vehicles, which are applied toaffected portions of the skin.

The dosage requirements vary with the particular compositions employed,the route of administration, the severity of the symptoms presented andthe particular subject being treated. Treatment will generally beinitiated with small dosages less than the optimum dose of the compound.Thereafter the dosage is increased until the optimum effect under thecircumstances is reached. In general, the compounds of the invention aremost desirably administered at a concentration that will generallyafford effective results without causing any harmful or deleterious sideeffects, and can be administered either as a single unit dose, or ifdesired, the dosage may be divided into convenient subunits administeredat suitable times throughout the day.

The interleukin 1 antagonist activity of the compounds of the inventionmay be demonstrated by standard pharmacological procedures, which aredescribed more fully in the examples given hereinafter.

These procedures illustrate the ability of the compounds of theinvention to inhibit the IL1-induced release of neutral protease fromarticular chondrocytes.

The following examples show the preparation and pharmacological testingof compounds within the invention.

EXAMPLE 17-Chloro-3,4-dihydro-10-(2-phenylhydrazino)-1H-thiopyrano[4,3-b]quinolineA. 7,10-Dichloro-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline

To a slurry of 14.8 g (0.0863 mol) of 2-amino-4-chlorobenzoic acid and150 ml of phosphorous oxychloride is added dropwise 10 g (0.086 mol) oftetrahydrothiopyran-4-one. The mixture is stirred at reflux for 3 hoursand then concentrated in vacuo. The residue is dissolved in methylenechloride and added slowly to an ice-NH₄ OH mixture. The mixture isstirred for 1/2 hour and extracted with methylene chloride. The combinedextracts are washed with water, dried over Na₂ SO₄, and concentrated invacuo to yield a dark solid. Trituration with ether furnishes 15 g (64%)of title compound: m.p. 112°-115° C.; IR (KBr) 1605, 1480, and 1415 cm⁻¹; NMR (CDCl₃) δ8.08-8.02 (m, 2H), 7.58-7.52 (m, 1H), 4.08 (s, 2H), 3.44(t, 2H), and 3.08 (t, 2H).

Analysis for: C₁₂ H₉ NCl₂ S

Calculated: C, 53.34; H, 3.36; N, 5.19.

Found: C, 52.98; H, 3.51; N, 5.61.

B.7-Chloro-3,4-dihydro-10-(2-phenylhydrazino)-1H-thiopyrano[4,3-b]quinoline

A mixture of 4.0 g (0.015 mol) of the compound of step A, above, 3.2 ml(0.03 mol) of phenylhydrazine, 2.5 ml of concentrated hydrochloric acid,and 150 ml of absolute ethanol is stirred under reflux for 6 hours. Theprecipitate, on cooling, is collected and dissolved in methanol.Treatment with a Na₂ CO₃ solution yields an off-white solid.Recrystallization from toluene/hexane furnishes 575 mg (11%) of titlecompound: m.p. 201°-202° C.; IR 3300, 3240, 1605, and 1560 cm⁻¹ ; NMR(DMSO-d₆) δ8.68-8.58 (m, 1H), 8.50 (s, 1H, exchangeable), 8.28 (s, 1H,exchangeable), 7.86-7.8 (m, 1H), 7.46-7.38 (m, 1H), 7.24-6.94 (m, 2H),6.86-6.72 (m, 3H), 4.04 (s, 2H), 2.20 (t, 2H), and 1.96 (t, 2H).

Analysis for: C₁₈ H₁₆ N₃ ClS

Calculated: C, 63.24; H, 4.72; N, 12.29.

Found: C, 63.59; H, 4.82; N, 11.93.

EXAMPLE 26-Chloro-1,2,3,4-tetrahydro-2-methyl-9-(2-phenylhydrazino)acridine A.6,9-Dichloro-1,2,3,4-tetrahydro-2-methylacridine, quarter hydrate

To a slurry of 15.3 g (0.0892 mol) of 2-amino-4-chlorobenzoic acid and150 ml of phosphorous oxychloride is added dropwise 10 g (0.0892 mol) of4-methylcyclohexanone. The mixture is stirred at reflux for 3 hours andthen concentrated in vacuo. The residue is dissolved in methylenechloride and added slowly to an ice-NH₄ OH mixture. The mixture isstirred for 1/2 hour and extracted with methylene chloride. The combinedextracts are washed with water, dried over Na₂ SO₄, and concentrated invacuo to yield a dark solid. Trituration with ether affords 14.2 g (60%)of title compound: m.p. 85°-87° C.; IR (KBr) 2920, 1605, 1585, 1480, and1420 cm⁻¹ ; NMR (CDCl₃) δ8.12-8.0 (m, 2H), 7.50-7.42 (m, 1H), 3.18-3.02(m, 3H), 2.32-2.20 (m, 1H), 2.12-1.92 (m, 2H), 1.66-1.48 (m, 1H), and1.2 (d, 3H).

Analysis for: C₁₄ H₁₃ NCl₂ ·1/4 H₂ O

Calculated: C, 62.12; H, 5.02; N, 5.18.

Found: C, 62.41; H, 4.92; N, 5.49.

B. 6-Chloro-1,2,3,4-tetrahydro-2-methyl-9-(2-phenylhydrazino)acridine

A mixture of 4.0 g (0.015 mol) of the compound of step A, above, 3.2 ml(0.03 mol) of phenylhydrazine, 2.5 ml of concentrated hydrochloric acid,and 150 ml of absolute ethanol is stirred under reflux for 6 hours. Theprecipitate, on cooling, is collected and dissolved in methanol.Treatment with a Na₂ CO₃ solution yields an off-white solid.Recrystallization from toluene/hexane furnishes 1.1 g (22%) of titlecompound: m.p. 197°-199° C.; IR (KBr) 3330, 3240, 1605, 1555 and 1485cm⁻¹ ; NMR (DMSO-d₆) δ8.78-8.70 (m, 1H), 8.18 (s, 1H, exchangeable),8.08 (s, 1H, exchangeable), 7.76-7.70 (m, 1H), 7.28-7.22 (m, 1H),7.20-7.12 (m, 2H), 6.84-6.70 (m, 3H), 3.06-2.88 (m, 3H), 2.38-2.24 (m,1H), 1.98-1.78 (m, 2H), 1.54-1.38 (m, 1H), and 1.08 (d, 3H).

Analysis for: C₂₀ H₂₀ N₃ Cl

Calculated: C, 71.10; H, 5.97; N, 12.44.

Found: C, 71.12; H, 6.10; N, 12.09.

EXAMPLE 36-Chloro-1,2,3,4-tetrahydro-2-phenyl-9-(2-phenylhydrazino)acridine A.6,9-Dichloro-1,2,3,4-tetrahydro-2-phenylacridine, hemihydrate

To a slurry of 15 g (0.0874 mol) of 2-amino-4chlorobenzoic acid and 150ml of phosphorous oxychloride is added dropwise 15 g (0.0871 mol) of4-phenylcyclohexanone. The mixture is stirred at reflux for 3 hours andthen concentrated in vacuo. The residue is dissolved in methylenechloride and added slowly to an ice-NH₄ OH mixture. The mixture isstirred for 1/2 hour and extracted with methylene chloride. The combinedextracts are washed with water, dried over Na₂ SO₄, and concentrated invacuo to yield a dark solid. Trituration with ether provides 20 g (70%)of title compound: m.p. 134°-136° C.; IR 1605, 1585 and 1480 cm⁻¹ ; NMR(CDCl₃) δ8.12-8.0 (m, 2H), 7.54-7.46 (m, 1H), 7.44-7.26 (m, 5H),3.50-2.88 (m, 5H), and 2.28-2.02 (m, 2H).

Analysis for: C₁₉ H₁₅ NCl₂ ·1/2 H₂ O

Calculated: C, 67.66; H, 4.78; N, 4.15.

Found: C, 67.56; H, 4.57; N, 4.58.

B. 6-Chloro-1,2,3,4-tetrahydro-2-phenyl-9-(2-phenylhydrazino)acridine

A mixture of 5.22 g (0.0159 mol) of the compound of step A, above, 3.2ml (0.03 mol) of phenylhydrazine, 2.5 ml of concentrated hydrochloricacid, and 150 ml of absolute ethanol is stirred under reflux for 6hours. The precipitate on cooling is collected and dissolved inmethanol. Treatment with Na₂ CO₃ solution yields an off-white solid.Recrystallization from toluene/hexane furnishes 2.7 g (42%) of titlecompound: m.p. 198°-199° C.; IR (KBr) 3320, 3240, 1605, 1555 and 1485cm⁻¹ ; NMR (DMSO-d₆) δ8.84-8.76 (m, 1H), 8.22 (s, 1H, exchangeable),8.16 (s, 1H, exchangeable), 7.78-7.72 (m, 1H), 7.46-7.12 (m, 8H),6.87-6.70 (m, 3H), 3.28-2.74 (m, 5H), and 2.18-1.90 (m, 2H).

Analysis for: C₂₅ H₂₂ N₃ Cl

Calculated: C, 75.08; H, 5.55; N, 10.51.

Found: C, 74.88; H, 5.60; N, 10.74.

EXAMPLE 4 10-Chloro-3,4-dihydro-1H-thiopyrano[4,3,-b]quinoline

A slurry of 10 g (0.0807 mol) of tetrahydrothiopyranone, 11.8 g (0.0807mol) of anthranilic acid, and 150 ml of phosphorous oxychloride isstirred at 100° C. for 5 hours, cooled, and concentrated in vacuo. Theresidue is dissolved in methylene chloride and added slowly to anice-NH₄ OH mixture. The aqueous phase is separated and extracted withmethylene chloride. The combined organic phases are dried over Na₂ SO₄and concentrated in vacuo to give a waxy solid. Trituration with ethylether furnishes 11.2 g (59%) of the title compound: IR (KBr) 1575, 1550,and 1480 cm⁻¹ ; NMR (DMSO-d₆) δ8.18-7.66 (m, 4H), 4.04 (s, 2H), 3.30 (t,2H), and 3.02 (t, 2H).

Analysis for: C₁₂ H₁₀ NSCl

Calculated: C, 61.14; H, 4.28; N, 5.94.

Found: C, 61.50; H, 4.39; N, 5.93.

EXAMPLE 53,4-Dihydro-10-(2-phenylhydrazino)-1H-thiopyrano[4,3-b]quinoline,three-quarters hydrate

A mixture of 4.0 g (0.017 mol) of the compound of Example 4, 3.65 ml(3.68 g/0.034 mol) of phenylhydrazine, 150 ml of ethanol, and 2 ml ofconcentrated hydrochloric acid is stirred at reflux for 6 hours, thenallowed to cool to ambient temperature. The resulting precipitate isdissolved in methanol and this solution is treated with Na₂ CO₃solution. The resulting precipitate is collected and triturated withethyl ether to afford 980 mg (18%) of the title compound: IR (KBr) 3280,3200, 1590, 1560, 1525, and 1490 cm⁻¹ ; NMR (DMSO-d₆) δ8.58-6.7 (complexm, 9H), 8.36 (br-s, 1H, exchangeable), 8.20 (br-s, 1H, exchangeable),4.08 (s, 2H), 3.18 (t, 2H), and 2.94 (t, 2H).

Analysis for: C₁₈ H₁₇ N₃ S·3/4 H₂ O

Calculated: C, 67.36; H, 5.81; N, 13.09.

Found: C, 67.36; H, 5.42; N, 12.77.

EXAMPLE 6 10-Chloro-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline2,2-dioxide

To a mixture of 3 g (0.0127 mol) of the compound of Example 4 and 100 mlof chloroform is added dropwise a solution of 6.04 g (0.028 mol) ofm-chloroperoxybenzoic acid and 100 ml of chloroform. The reactionmixture is stirred for one hour, washed with Na₂ CO₃ solution, driedover Na₂ SO₄, and concentrated in vacuo to give a pasty solid.Trituration with ethyl ether furnishes 1.1 g (32%) of the titlecompound; IR (KBr) 1480, 1320, and 1120 cm⁻¹ ; NMR (DMSO-d₆) δ8.30-7.6(complex m, 4H), 4.75 (s, 2H), 3.4-3.10 (complex m, 4H).

Analysis for: C₁₂ H₁₀ NClO₂ S

Calculated: C, 53.83; H, 3.77; N, 5.23.

Found: C, 53.90; H, 3.83; N, 5.59.

EXAMPLE 7 7,10-Dichloro-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline2,2-dioxide

To a mixture of 3 g (0.0111 mol) of the compound of Example 1A, above,and 100 ml of chloroform is added dropwise a solution of 5.27 g (0.0244mol) of m-chloroperoxybenzoic acid and 100 ml of chloroform. Thereaction mixture is stirred for one hour, washed with Na₂ CO₃ solution,dried over Na₂ SO₄ and concentrated in vacuo to give a pasty solid.Trituration with ethyl ether affords 2.65 g (79%) of the title compound:IR (KBr) 1600, 1580, 1540, 1470, 1400, 1305, and 1120 cm⁻¹ ; NMR(DMSO-d₆) δ8.30-7.60 (m, 3H), 4.75 (s, 2H), and 3.40-3.05 (m, 4H).

Analysis for: C₁₂ H₉ NCl₂ O₂ S·1/4 H₂ O

Calculated: C, 46.99; H, 3.12; N, 4.57.

Found: C, 46.79; H, 3.09; N, 4.46.

EXAMPLE 87-Chloro-3,4-dihydro-10-(2-phenylhydrazino)-1H-thiopyrano[4,3-b]quinoline2,2-dioxide

To a solution of 110 mg (0.00032 mol) of the compound of Example 1B,above, and 25 ml of chloroform is added dropwise a solution of 185 mg(0.00087 mol) of m-chloroperoxybenzoic acid and 25 ml of chloroform. Thereaction mixture is stirred for one hour, washed with Na₂ CO₃ solution,dried over Na₂ SO₄, and concentrated in vacuo. Trituration with ethylether affords 32 mg (27%) of the title compound: IR (KBr) 3400 (br),3080, 3000, 1600, 1310, 1295, and 1130 cm⁻¹ ; NMR (DMSO-d₆) δ8.18-7.68(m, 10H), 4.72 (s, 2H), 3.78-3.64 (m, 4H).

Analysis for: C₁₈ H₁₆ N₃ ClSO₂

Calculated: C, 57.83; H, 4.31; N, 11.24.

Found: C, 58.46; H, 4.02; N, 10.96.

EXAMPLE 9 6,9-Dichloro-1,2,3,4-tetrahydro-2-acridinecarboxylic acidmethyl ester

To a slurry of 16.5 g (0.096 mol) of 4-chloroanthranilic acid and 166 mlof phosphorous oxychloride is added portionwise 15 g (0.096 mol) ofmethyl 4-ketocyclohexane carboxylate. The reaction mixture is refluxedfor 3 h, cooled, and concentrated in vacuo. The residue is dissolved inmethylene chloride and poured into an ice-NH₄ OH mixture. The aqueousphase is separated and extracted with methylene chloride. The combinedorganic phases are dried over Na₂ SO₄ and concentrated in vacuo. Theresidue is triturated with ethyl ether to give 21.7 g (73%) of the titlecompound: IR (KBr) 1730, 1605, 1580, and 1550 cm⁻¹ ; NMR (DMSO-d₆)δ8.14-8.08 (m, 1H), 8.0-7.96 (m, 1H), 7.70-7.64 (m, 1H), 3.70 (s, 3H),3.30-3.16 (m, 1H), 3.12-2.96 (m, 4H), 2.32-2.20 (m, 1H), and 2.04-1.86(m, 1H).

Analysis for: C₁₅ H₁₃ Cl₂ NO₂

Calculated: C, 58.08; H, 4.22; N, 4.52.

Found: C, 57.88; H, 4.41; N, 4.59.

EXAMPLE 106-Chloro-1,2,3,4-tetrahydro-9-(2-phenylhydrazino)-2-acridinecarboxylicacid ethyl ester

A mixture of 11 g (0.035 mol) of the compound of Example 9, 7.1 g (0.066mol) of phenylhydrazine, 5.5 ml of conc. hydrochloric acid, and 330 mlof ethanol is heated at reflux overnight. On cooling, the resultingprecipitate is collected, and dissolved in methanol. This solution istreated with saturated Na₂ CO₃ solution. The resulting solid iscollected, washed with water and triturated with methylenechloride-ethyl acetate to give 5.7 g (41%) of solid. Recrystallizationfrom isopropanol affords 794 mg (6%) of the title compound: mp 181°-182°C.; IR (KBr) 3320, 3240, 1720, 1605, and 1550 cm⁻¹ ; NMR (DMSO-d₆) δ8.24(br-s, 1H, exchangeable), 8.18 (br-s, 1H, exchangeable), 7.32-7.22 (m,1H), 7.20-7.16 (m, 3H), 6.86-6.68 (m, 4H), 4.10 (q, 2H), 3.16-2.80 (m,5H), 2.20-2.06 (m, 1H), 1.96-1.84 (m, 1H), and 1.16 (t, 3H).

Analysis for: C₂₂ H₂₂ ClN₃ O₂

Calculated: C, 66.74; H, 5.60; N, 10.62.

Found: C, 66.83; H, 5.48; N, 10.49.

EXAMPLE 11 6,9-Dichloro-1,2,3,4-tetrahydro-2-acridinecarboxylic acid

A mixture of 9.9 g (0.032 mol) of the compound of Example 9, 3.25 ml ofethanol, 32.5 ml of water, and 2.6 g of NaOH is stirred overnight atambient temperature. The resulting solid is collected, washed with ethylacetate, then dissolved in 100 ml of water. The solution is acidifiedwith acetic acid and the resulting precipitate is collected, washedcopiously with water and dried to give 6.64 g (70%) of the titlecompound: mp >250° C.; IR (KBr) 2900 (br), 2500 (br), 1700 (br), 1600,1540, and 1470 cm⁻¹ ; NMR (DMSO-d₆) δ12.6 (br-s, 1H, exchangeable),7.92-7.86 (m, 1H), 7.82-7.76 (m, 1H), 7.54-7.48 (m, 1H), 3.10-2.76 (m,5H), 2.28-2.12 (m, 1H), and 1.94-1.88 (m, 1H).

Analysis for: C₁₄ H₁₁ Cl₂ NO₂

Calculated: C, 56.78; H, 3.74; N, 4.73.

Found: C, 56.85; H, 3.92; N, 4.82.

EXAMPLE 126-Chloro-1,2,3,4-tetrahydro-9-(2-phenylhydrazino)-2-acridinecarboxylicacid hemihydrate

A mixture of 2.0 g (0.0051 mol) of the compound of Example 10, 6.4 ml ofwater, 6.4 ml of ethanol, and 0.4 g of NaOH is stirred at ambienttemperature overnight, then concentrated in vacuo. The residue isdissolved in water and extracted with ethyl acetate. The aqueous phaseis acidified using acetic acid and extracted with methylene chloride.The organic extracts are dried over Na₂ SO₄, and concentrated in vacuo.The resulting powder is triturated with petroleum ether to give 42 mg ofthe title compound: IR (KBr) 3250 (br), 2940 (br), 2500 (br), 1700 , and1600 cm⁻¹ ; NMR (DMSO-d₆) δ8.18-7.58 (m, 11H), 3.24-2.90 (m, 5H),2.38-2.22 (m, 1H), and 2.10-1.98 (m, 1H).

Analysis for: C₂₀ H₁₈ ClN₃ O₂ ·1/2 H₂ O

Calculated: C, 63.74; H, 5.08; N, 11.15.

Found: C, 63.57; H, 4.55; N, 10.59.

EXAMPLE 13

The ability of the compounds of the inventions to inhibit interleukin 1is measured by the ability of the test compounds to inhibit the IL1-induced release of neutral protease from rabbit articularchondrocytes.

This assay is carried out as follows:

Isolation of rabbit chondrocytes:

Male New Zealand White rabbits are anesthetized with 50 mg/kg ofketamine (i.m.) and killed by an intracardiac injection of 3 mls ofNembutal. The knee joints of both legs are resected and the articularsurfaces are exposed. Cartilage slices are obtained using a scalpel andare placed in a tissue culture dish (100 mm diameter) containing 10 mlsof Hank's balanced salt solution (HBSS). The chondrocytes within thecartilage slices are then liberated by a series of enzyme digestions.The slices are incubated for 10 minutes at 37° C. in 0.05% hyaluronidase(Sigma H-3884), rinsed with HBSS and incubated with 0.2% trypsin (SigmaT-2395) for 10 minutes at 37° C. The slices are rinsed again andincubated for 10 minutes at 37° C. with 1.2% collagenase (Sigma C-5138).The slices are then rinsed again with HBSS and resuspended in 10 ml ofHam's F-12 medium containing 10% fetal bovine calf serum (FCS) and 0.2%collagenase and incubated overnight at 37° C. in a 5% CO₂ incubator. Thenext day, the medium containing the digested cartilage fragments andliberated chondrocytes is transferred to a 15 ml centrifuge tube and thecells are collected by centrifugation and washed twice and resuspendedin Ham's F-12 medium. The cells are then plated into 24-well tissueculture plates (2×10⁵ cells/well) and incubated at 37° C. untilconfluent (usually 4-6 days).

Stimulation of chondrocytes and drug treatment:

The confluent chondrocytes are rinsed twice with serum-free Ham's F-12medium and 1 ml is added to each well. Fifty μl of purified human IL 1(100 Units/ml; Genzyme Corporation, Boston, Mass.) is then added tostimulate these cells to secrete neutral protease. To measure drugeffects, the cells are treated with test compound 10 minutes prior toaddition of IL 1. The standard screening dose is 10 μM. Twenty-fourhours after IL 1 stimulation, supernatant fluids are collected andassayed for neutral protease activity.

Neutral protease assay:

The neutral protease activity of chondrocyte supernatant fluids isdetermined by their ability to degrade an insoluble protease substrate,azocoll (Sigma). Supernatants are treated for 10 minutes at roomtemperature with 350 μM p-aminophenylmurcuric acetate to activate thelatent enzyme. Three hundred μl of supernatant is then mixed with 500 μlof a 20 mg/ml suspension of azocoll and incubated at 37° C. for 18-24hours with gentle rocking. The mixtures are centrifuged and the amountof substrate hydrolyzed is determined by measuring the absorbance of thesupernatant at 520 nm.

Drug effects are calculated as the % change in enzyme activity(absorbance) by supernatants from drug-treated chondrocytes relative toenzyme activity of supernatants from vehicle-treated chondrocytes asfollows: ##EQU1## Where tested in this assay, the compounds of theinvention gave the following results, showing them to exhibit a moderateto very significant inhibition of IL 1-induced protease secretion:

    ______________________________________                                        Compound of    Dose    % Inhibition                                           Example No.    (μM) (I.S.D.)                                               ______________________________________                                        1A             10      35 ± 11                                             1B             10      98 ± 1                                                             5       93 ± 5                                                             1       94                                                                    0.1     67                                                     2A             10      34 ± 26                                             2B             10      85 ± 6                                                             1       36                                                     3A             10      ≦20                                             3B             10      81 ± 2                                                             1       27                                                     4              10      43                                                                    5       46                                                                    1       38                                                     5              10      79 ± 14                                                            5       55 ± 22                                                            1       37 ± 0                                              6              10      32                                                                    5       19                                                     7              10      25                                                                    5       26                                                                    1       10                                                     8              10      16                                                                    5       37                                                                    1        3                                                     9              10      58                                                                    5       53                                                                    1       30                                                     10             10      96                                                                    1       91                                                                    0.1     70                                                     11             10      88                                                                    1       50                                                                    0.1     58                                                     12             10      68                                                                    1       61                                                                    0.1     57                                                     ______________________________________                                    

What is claimed is:
 1. A compound having the formula ##STR10## wherein Xis O, S, SO or SO₂ ;R⁴ is halo, morpholino, 4-methylpiperazino, R⁵NNHR⁶, or ##STR11## R⁵ is hydrogen or lower alkyl; R⁶ is hydrogen, loweralkyl, lower alkanoyl, lower cycloalkyl or phenyl; and R⁷ and R⁸ areeach independently, hydrogen, halo, nitro, lower alkoxy, lower alkyl,cyano, trifluoromethyl, phenyl, carboxy or lower alkoxycarbonyl.
 2. Thecompound of claim 1, having the name7-chloro-3,4-dihydro-10-(2-phenylhydrazino)-1H-thiopyrano[4,3-b]quinoline.
 3. The compound of claim 1, having the name10-chloro-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline.
 4. The compound ofclaim 1, having the name3,4-dihydro-10-(2-phenylhydrazino)-1H-thiopyrano[4,3-b]quinoline.
 5. Thecompound of claim 1, having the name10-chloro-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline 2,2-dioxide.
 6. Thecompound of claim 1, having the name7,10-dichloro-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline 2,2-dioxide. 7.The compound of claim 1, having the name7-chloro-3,4-dihydro-10(2-phenylhydrazino)-1H-thiopyrano[4,3-b]quinoline2,2-dioxide.
 8. The compound of claim 1, having the name7,10-dichloro-3,4-dihydro-1H-thiopyrano[4,3-b]quinoline.